Hyperphosphataemia
Hyperphosphataemia is an electrolyte disturbance in which there is an abnormally elevated level of phosphate in blood. Hyperphosphataemia is frequently seen in dialysis patients, as standard dialysis regimes are unable to remove the ingested phosphate load even with a low phosphate diet, and is associated with an increased risk of death and the development of vascular calcification. The presence of hyperphosphataemia leads to hypocalcaemia, secondary hyperparathyroidism, reduced 1.25 Vit D3 and progressive metabolic bone disease Hyperphosphataemia is ultimately responsible for the increase in vascular calcification, but recent studies have also suggested that the process may additionally be influenced by 1.25 Vit D3 and an elevated calcium-phosphate product. Patients who have chronically uncontrolled hyperphosphataemia develop progressively extensive soft tissue calcifications due to the deposit of Calcium/phosphate product into skin, joints, tendons, ligaments. Eye deposits of calcium/phosphate product have also been described.
Control of serum phosphate levels using oral phosphate binders has, therefore, become a key therapeutic target in the management of dialysis patients. These binders, taken with food, render the contained phosphate insoluble and, therefore, non-absorbable.
Phosphate Binders
Historically phosphate binders included aluminium salts. However, use of aluminium salts was found to result in further toxic complications due to aluminium accumulation, e.g. reduction in haemoglobin production, impairment in natural repair and production of bone and possible impairment of neurological/cognitive function. Renal bone disease, osteomalacia and dementia are the most significant toxicities related to the absorption of aluminium. Other aluminium compounds such as microcrystalline aluminium oxide hydroxide (boehmite) and certain hydrotalcites were proposed for this use, such as disclosed in Ookubo et al, Journal Pharmaceutical Sciences (November 1992), 81 (11), 1139-1140. However these suffer from the same drawbacks.
Calcium carbonate or calcium acetate are used as phosphate binders. However these suffer from the drawback that they tend to promote hypocalcaemia through the absorption of high amounts of ingested calcium and are linked to accelerated cardiovascular calcification which can cause serious side effects. Consequently, frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders. The National Kidney Foundation Kidney Disease Quality Outcomes Initiative suggests the limited use of calcium based salts (Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guide 5, pg 1 pt 5.5). Recent efforts, therefore, have focused on the development of phosphate binders free of calcium. More recently, lanthanum carbonate and sevelamer HCl have been used as calcium-free phosphate binders. Sevelamer hydrochloride is a water-absorbing, non-absorbed hydrogel-cross-linked polyallylamine hydrochloride but because of its structure also binds certain fat-soluble vitamins and bile acids and is therefore reported in V Autissier et al, Journal of Pharmaceutical Sciences, Vol 96, No 10, October 2007 to require large doses to be effective because it has a higher propensity for the bound phosphate to be displaced by these competing anions. A high pill burden or large tablets are often associated with poor patient compliance and this type of product is also considered relatively expensive to their calcium counter parts. Sevelamer has also been associated with GI adverse effects A. J. Hutchison et al, Drugs 2003; 63 (6), 577-596.
Lanthanum carbonate is a phosphate binder which has been shown to be as effective as calcium carbonate with lower incidence of hypocalcaemia. Long-term administration of lanthanum, a rare earth element, continues to raise safety concerns with regards to the potential accumulation of a rare earth metal in body tissue which can be enhanced in renal failure—Tilman B Druke, Seminars in Dialysis, Volume 20, Issue 4 page 329-332 July/August 2007
Many known inorganic preparations for treatment of hyperphosphataemia are efficient phosphate binders only over a limited pH range. Moreover, particularly alkaline binders could buffer the stomach pH up to a high level at which they would not have a phosphate binding capacity.
To overcome the drawbacks associated with aluminium and also problems of efficacy over a limited pH range, WO-A-99/15189 discloses use of mixed metal compounds which are free from aluminium and which have a phosphate binding capacity of at least 30% by weight of the total weight of phosphate present, over a pH range of from 2-8.
Mixed Metal Compounds
Mixed metal compounds (mixed metal compounds) exist as so-called “Layered Double Hydroxide” (LDH) which is used to designate synthetic or natural lamellar hydroxides with two kinds of metallic cations in the main layers and interlayer domains containing anionic species. This wide family of compounds is sometimes also referred to as anionic clays, by comparison with the more usual cationic clays whose interlamellar domains contain cationic species. LDHs have also been reported as hydrotalcite-like compounds by reference to one of the polytypes of the corresponding [Mg—Al] based mineral. (See “Layered Double Hydroxides: Present and Future”, ed, V Rives, 2001 pub. Nova Science).
By mixed metal compound, it is meant that the atomic structure of the compound includes the cations of at least two different metals distributed uniformly throughout its structure. The term mixed metal compound does not include mixtures of crystals of two salts, where each crystal type only includes one metal cation. Mixed metal compounds are typically the result of coprecipitation from solution of different single metal compounds in contrast to a simple solid physical mixture of two different single metal salts. Mixed metal compounds as used herein include compounds of the same metal type but with the metal in two different valence states e.g. Fe(II) and Fe(III) as well as compounds containing more than two different metal types in one compound.
The mixed metal compound may also comprise amorphous (non-crystalline) material. By the term amorphous is meant either crystalline phases which have crystallite sizes below the detection limits of x-ray diffraction techniques, or crystalline phases which have some degree of ordering, but which do not exhibit a crystalline diffraction pattern and/or true amorphous materials which exhibit short range order, but no long-range order.
Mixed metal compounds provide unique challenges in using inorganic material for pharma use and in particular for phosphate binding and which are free of Al.
For example, use of mixed metal compound for attaining phosphate therapeutic effects (or other pharma functional use) depends on surface processes such as physisorption (ion-exchange) and chemisorption (formation of a chemical bond) which is atypical for a drug; the therapeutic activity of most drugs are based on organic compounds which are typically more soluble.
Yet further, high daily and repeated long-term (chronic) dosages are required for kidney patients but their total daily pill count requires a low tablet burden due to restricted fluid intake. Consequently, high dosage of drug substance is required in final product (e.g. tablet) and the final product is therefore very sensitive to the properties of the mixed metal compound drug substance, unlike normal formulations. This means that the properties of the tablet, including key physical properties, and the tablet manufacturing processes, such as granulation, are often primarily influenced by the properties of the mixed metal compound active substance rather than solely by those of the excipients. In order to be able to manufacture a pharmaceutical product comprising such significant quantities of mixed metal compound with the control and consistency necessary for pharmaceutical use, a means of controlling an array of opposing chemical and physical properties of the mixed metal compound is essential.
Therefore, considering these requirements, manufacture of such materials, particularly at large scale, presents significant problems. A number of these problems are described below.
Ageing
The ageing process (growth of crystallites) generally increases with (unintended) increased processing and handling as well as by the process whereby the crystallites are intentionally grown by a combination of agitation and heat-treatment of the reaction slurry before filtration. Control and prevention of crystal growth can therefore be difficult.
The teachings of MgAl mixed metal compounds which are manufactured in the aged form for medical applications such as antacids, do not address the problems of manufacture of unaged mixed metal compounds (on a larger scale), when the unaged form is required, for example to maintain therapeutic activity of phosphate binding. Furthermore, when replacing Al for Fe we found that the mixed metal compound changes properties such as to becoming more difficult to wash and mill on a commercial scale.
Al-containing mixed metal compounds that are intentionally aged to increase crystal growth have previously been manufactured on a large scale. In contrast, there appear to be no examples of large scale manufacture of unaged Al-free mixed metal compounds.
The method disclosed in WO99/15189 relates to Al free mixed metal compounds and includes examples of unaged and aged materials. However, the products disclosed in this publication are provided at relatively small scale. WO99/15189 does not address the problems of provision of product at significant scale while avoiding aging of the product.
The manufacture of unaged mixed metal Mg:Fe compounds (Mg:Fe defined by molar ratio hereinafter) on a large scale is problematic for a number of reasons. For example, the manufacture of unaged mixed metal Mg:Fe compounds is problematic when using conventional filtration methods. Unaged material results in a high pressure drop through the filter cake during isolation leading to low filtration rates or yield losses during conventional filtration. Furthermore, these types of metal Mg:Fe compounds typically have small slurry particle size and as such it is difficult to carry out isolation whilst minimising ageing. For example, small particles can give rise to increased processing times and/or handling issues.
Furthermore, too much processing and handling (e.g. milling and overdrying) can present changes that are unacceptable in the final mixed metal Mg:Fe compound. In particular with such compounds, it is important to dry the material carefully as it is easy to change the surface area or internal pore volume and hence change the therapeutic activity. These typical morphology properties are important characteristics affecting both the quality of the final mixed metal compound and the downstream manufacturing processes used to produce the final formulated pharmaceutical product containing the mixed metal compound.
If processed incorrectly mixed metal compounds can become unacceptably hard. This can lead to consequent issues of decreased milling rates and higher energy input to achieve a given particle size. This ‘knock on’ effect to the processing may affect process throughput and result in overworking the material and consequential ageing.
Methods for lab-scale preparations of MgFe LDH's are disclosed in art such as U.S. Pat. No. 4,629,626; Duan X, Evans D. G., Chem. Commun., 2006, 485-496; W. Meng at al, J Chem. Sci., Vol. 117, No. 6 Nov. 2005, pp. 635-639; Carlino, Chemistry between the sheets, Chemistry in Britain, September 1997, pp 59-62; Hashi et al, Clays and Clay Minerals (1983) pp 152-15; Raki et al, 1995, 7, 221-224; Ookubo et al, Langmuir (1993), 9, pp 1418-1422I; Zhang et al. Inorganic Materials Vol 0.4 March 132-138 (1997), Reichle, Solid States Ionics, 22, pp 135-141 (1986); Ulibarri at al, Kinetics of the Thermal Dehydration of some layered Hydrocycarbonates, Thermochimica Acta, pp 231-236 (1988); Hansen et al, Applied Clay Science 10 (1995) pp 5-19.
These methods describe lab-scale preparations only. Furthermore, these materials are obtained via a process which includes an ageing step (i.e. a deliberate process of increasing crystal growth which is typically achieved by heating the reaction slurry over a prolonged period of time such as by a hydrothermal process). In general, the compounds of the prior art also contain substantially more than one type of anion in the interlayer region.
Methods for large scale manufacturing of MgAl hydrotalcites are disclosed in art such as U.S. Pat. No. 3,650,704, WO-A-2008/129034 and WO-A-93/22237. However, these describe the process for obtaining materials in the aged form resulting in a larger crystallite size (of above 200 Angstrom) and are not free of aluminium.
Aspects of the invention are defined in the appended claims.